1. Natural Killer Cell Inhibitory Receptors CD94/NKG2, with its cytoplasmic immuno-tyrosine inhibitory motif (ITIM), defines a family of MHC class I molecule mediated negative/positive signaling receptors on the surface of natural killer (NK) cells. Both chains are members of the type II transmembrane C-lectin family of receptors. Recently, the ligand of this receptor family has been identified to be HLA-E, which presents the signal peptides of other class I MHC molecules. We have expressed and reconstituted several forms of CD94 and NKG2A extracellular ligand binding domains. The crystallization of CD94 yielded crystals diffracting to 2.6 angstrom resolution. The structure of CD94 revealed a novel C-type lectin fold with the second canonical C-type lectin alpha helix being distorted into a looped conformation to form a CD94/CD94 dimer interface. Another family of inhibitory receptors, termed Killer Immunoglobulin-like Receptors (KIR), has been identified recently on the surface of human NK cells to mediate self versus non-self recognitions. To understand the function of these receptors, we have expressed and reconstituted a truncated form of KIR2DL2, using a bacteria expression system and in vitro refolding. We have previously determined the crystal structure of the receptor. Recently, we just completed the crystal structure of the KIR2DL2 in complex with its ligand HLA-Cw3. KIR binds in a nearly orthogonal orientation across the alpha1 and alpha2 helices of Cw3,directly contacting positions 7 and 8 of the peptide. No significant conformational changes in KIR are observed upon complex formation. The receptor footprint on HLA overlaps with, but is distinct from that of the T-cell receptor. Charge complementarity dominates the KIR/HLA interface and mutations disrupting interface salt bridges seriously diminished binding. While most KIR contacts are to conserved HLA-C residues, a hydrogen bond between Lys 44 of KIR2DL2 and Asn 80 of Cw3 confers the allotype specificity. KIR contact requires that P8 of the peptide to residues smaller than Val. A second KIR/HLA interface produced an ordered receptor-ligand aggregation in the crystal which may resemble receptor clustering during immune synapse formation.